The present invention relates to a method of treatment of postoperative and posttraumatic patients for improving the glutamine content in skeletal muscle by administrating alpha-ketoglutarate. The invention also relates to a composition for carrying out the method.
In states of illness, surgical operations and injuries, profound changes are induced in the energy and protein metabolism of the human body. This means, for example, loss of active cellular mass, leading to muscular fatigue, pronounced apathy and loss of appetite, and a period of convalescence involving general weariness which, for instance after a biliary tract operation, may last 5-6 weeks before the patient has regained his normal function. The cellular mass which is broken down very rapidly in different states of illness will need a time for reestablishment which is about four times as long as the time of breakdown for the same mass.
In severe states of illness and injuries, and in postoperative states, parenteral nutritional support is generally applied. In the past, preparations for intravenous nutritional support generally contained an aqueous solution of a high caloric content carbohydrate, such as glucose and the like, and electrolytes. In prolonged states of illness or in injuries and surgical operations, the nitrogen balance of the body must however be considered, i.e. the ratio of nitrogen loss to nitrogen intake. In the case of negative nitrogen balance, the parenteral nutritional support can be supplemented with an amino acid supply in an attempt to improve the nitrogen balance. Different amino acid compositions for parenteral supply are previously known, see e.g. SE Patent Application 8203965-2 and DE-A 25 30 246 concerning amino acid nutrient compositions in renal failure, WO 82/00411 concerning a nutrient composition containing branched-chain amino acids, and WO 83/03969 concerning an aqueous nutrient solution consisting of L-amino acids.
From a survey made of the free amino acid pattern in the muscles, it has been found that skeletal muscle, which is the major body tissue in respect of weight, has a free amino acid pool of which 62% consists of glutamine (see Bergstroem et al., "Intracellular free amino acid concentrations in human muscle tissue", J. of Appl. Physiol., Vol 36, No 6, 1974). In states of illness, injuries or surgical operations, this content decreases by at lest 50% and, in states of blood poisoning, even more (see Vinnars et al., "Influence of the postoperative state on the intracellular free amino acids in human muscle tissue", Annals of Surg., Vol 182, 6:665-671, 1975).
It has been found that this glutamine reduction cannot be affected by enteral or parenteral nutritional support according to the methods hitherto available (see Vinnars et al., "Metabolic effects of four intravenous nutritional regiments in patients undergoing elective surgery. 11. Muscle amino acids and energy rich phosphates", Clin. Nutr., 2:3-11, 1983). There is probably a correlation between the inability immediately postoperatively to make a negative nitrogen balance positive, the inability to normalize the exhausted intracellular glutamine pool, and the reduced muscular strength. This reduction probably depends on a reduced protein synthesis capacity postraumatically in skeletal muscle (see Wernerman et al., "Protein syntheses after trauma as studied by muscle ribosome profiles", Proceedings in the 7th ESPEN Congress. ED. Dietze et al, Karger, Basel).
The addition to the nutritional support of a dipeptide of the type ornithine-alpha-ketoglutarate to a commercial amino acid solution has been found to improve to some extent, but not to normalize, the intracellular glutamine pool (see Leander et al., "Nitrogen sparing effect of Ornicetil in the immediate postoperative state", Clin. Nutr. 4:43-51, 1985). However, this preparation is very expensive and it has not been possible so far to evaluate whether its use in parenteral nutrition confers a clinical advantage.
Postoperatively, the patient often exhibits loss of appetite, making it difficult to supply nutrition, although there are possibilities, by tube-feeding, of supplying different kinds of nutrient solutions. Since most patients do not tolerate this way of feeding, it becomes necessary to resort to intravenous feeding. The nutrition substrates available for energy metabolism are various sugar solutions and fatty emulsions, which today seem appropriate. However, the amino acid solutions available are inadequate, both because it is not possible to add tyrosine in sufficient amounts since this is a relatively insoluble amino acid, and because certain important amide derivatives of amino acids (e.g., glutamine and asparagine) cannot be included. This is due to difficulties in heat-sterilizing solutions of such amides, and also to the fact that the amides are unstable when stored. Another problem is that these compounds are relatively sparingly soluble and therefore require large amounts of water when being prepared.
After elective surgery, for instance biliary tract operations, it has been found that the negative nitrogen balance primarily depends on reduced protein synthesis which is assessed by determining the ribosome activity in skeletal muscle (see Wernerman et al., "Protein synthesis in skeletal muscle after abdominal surgery: The effect of total parenteral nutrition", JPEN, 1985). An increased protein breakdown occurs only in very severe traumas and primarily in septic states. This reduced protein synthesis capacity cannot be affected by conventional intravenous or enteral nutritional support.